High concentration topical insecticides containing pyrethroids

ABSTRACT

A topical insecticide preparation is provided which can be safe to use and avoids many common deleterious side effects of conventional topical insecticides. The topical insecticide contains a combination of a first pyrethroid insecticide effective for killing fleas, a second pyrethroid insecticide effective for killing ticks, and an insect growth regulator (IGR). The topical insecticide preparation can be packaged together or packaged so that the first and second pyrethroid insecticides are stored separately prior to administration of the insecticide preparation to the animal. The combination of the first and second pyrethroid insecticides with an insect growth regulator results in an insecticide preparation formulated to have enhanced insecticidal activity against fleas and ticks compared to the effectiveness of the first and second insecticides used alone. Further, the combination of the first and second pyrethroid insecticides with an insect growth regulator produces an insecticide preparation having enhanced insecticidal activity against fleas and ticks while advantageously minimizing the total amount of insecticide needed for its effectiveness.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/795,677, filed Apr. 28, 2006 and is a continuation-in-part of andclaims priority to U.S. application Ser. No. 11/181,344, filed Jul. 14,2005, now abandoned which is a continuation-in-part of U.S. applicationSer. No. 10/910,542, filed Aug. 3, 2004, now U.S. Pat. No. 7,345,092,which claims the benefit of U.S. Provisional Application No. 60/493,976,filed Aug. 8, 2003, and U.S. Provisional Application No. 60/554,563,filed Mar. 19, 2004, and is also a continuation-in-part of U.S.application Ser. No. 10/242,551, filed Sep. 12, 2002, now U.S. Pat. No.6,867,223. Priority is claimed to the applications listed above, whichare incorporated herein by reference.

BACKGROUND OF INVENTION

The invention relates generally to insecticides and more particularly toa topical insecticide, such as one suitable to use on house pets such asdogs.

The infestation of animals with fleas, ticks, flies and the like ishighly undesirable. Accordingly, it has become common to administer bothtopical and internal insecticides to livestock and pets. Topicalapplications can be desirable, in that many insecticides are acceptablysafe when used topically, but not when used internally. Also, many petowners are concerned about administering internal insecticides to theirpets.

Various topical insecticides have drawbacks. Some require a large volumeto be applied to the animal. This can cause considerable mess and canlead to an unpleasant smell. Additionally, if the dosage of a topicalinsecticide is in a large volume, it can be easily shaken off by theanimal, thereby reducing the effectiveness of the insecticideformulation. Also, when the animal is a house pet, there is a furthercomplication in that the insecticide should be safe for human contact.It should also not lead to staining of furniture, carpeting and thelike. Finally, even if safe, topical insecticides for house pets shouldnot be irritating or lead to rashes, hair loss or exhibit otherunpleasant side effects.

There is therefore a need for an improved topical insecticide thatovercomes drawbacks of the prior art.

SUMMARY OF THE INVENTION

Generally speaking, in accordance with the invention, a topicalinsecticide, particularly one for use on pets, especially dogs, isprovided. Formulations in accordance with the invention can be safe touse and can avoid many common deleterious side effects of conventionaltopical insecticides.

The invention provides a topical insecticide which contains acombination of insecticides and insect growth regulators which can beeffective to kill fleas, flea eggs, flea larvae, ticks, tick eggs, ticklarvae and tick nymphs. The selection of the combination of insecticidesand insect growth regulators produces an insecticide having highinsecticidal activity while allowing for a lower total amount ofinsecticide to be applied to the animal, compared to the effectivenessand amount required of the individual insecticides when used alone toachieve the same kill rate. The compositions derived herein can also beuseful to improve the speed of result and decrease the reoccurrence,compared to other formulations.

The invention can provide an insecticidal composition which contains acombination of a first insecticide component in an insecticidallyeffective amount to achieve at least, e.g., an 80%, preferably 90% killrate for fleas, a second insecticide component in an insecticidallyeffective amount to achieve at least, e.g. an 80%, preferably 90% killrate for ticks, and a growth regulating effective amount of an insectgrowth regulator (IGR). In certain embodiments of the invention, thesecond insecticide is not a neo-nicotinoid, which is considered onlyeffective against fleas. The combination of the two insecticidecomponents and the insect growth regulator increases the effectivenessof the first and second insecticide compared to the effectiveness of thefirst and second insecticides when used alone and reduces the effectiveamount of the first and second insecticide compared to the effectiveamount of the first and second insecticide when used alone.

In one embodiment of the invention, at least one of the two insecticidecomponents in the composition is a pyrethroid and in other preferredembodiments, the first and second insecticide components in thecomposition are pyrethroids. In a preferred embodiment of the invention,the first insecticide component in the composition comprises permethrinAlternative embodiments of the invention can include cyphenothrin orfenpropathrin. The second insecticide component comprises a(tetrahydro-3-furanyl)methylamine derivative of formula (1), identifiedbelow. Of course, it should be understood that the designations of whichof the two is the first and which is the second is arbitrary andinterchangeable. Also, the identification of an active ingredient, e.g.,permethrin, is intended to also refer to other pharmaceutically activeforms of the active ingredient, such as esters, salts, hydrochlorides,acid or base forms, isomers and so forth.

In another embodiment of the invention, the first insecticide componentcomprises permethrin or phenothrin. The second insecticide componentcomprises a chloronicotinyl insecticide, preferably acetamiprid. Otherchloronicotinyl insecticides that can be utilized in the insecticideformulation include, but are not limited to nitenpyram and imidacloprid,thiamethoxam, and clothianidin.

In another preferred embodiment of the invention, the first insecticidecomponent comprises permethrin or phenothrin, and the second insecticidecomponent comprises dinotefuran, acetamiprid, nitenpyram, imidacloprid,or bifenthrin. The second component is advantageously in combinationwith an isoparaffinic solvent such as Isopar®, available commerciallyfrom EXXON and/or tripropylene glycol methyl ether (TPM), dipropyleneglycol methyl ether, propylene glycol methyl ether, ethyl lactate,propylene carbonate and/or safflower oil. It should be noted that inembodiments where the second insecticide is dinotefuran, Isopar andsafflower oil are preferably not included in the solvent solution.

It has been determined that it is difficult to form a high concentrationof dinotefuran and permethrin or phenothrin and it is likely to resultin a solution that can be unstable when stored at room temperature forreasonable amounts of time. Accordingly, it was determined to bepreferable to package the insecticide composition in a manner so thatthe first insecticide and second insecticide are not permitted tointeract prior to application of the insecticide composition to theanimal and to keep these formulations separated until application. Thefirst and second insecticides can be stored separately from each otherin a package or container having two associated, preferably attached,but individual chambers to prevent the mixing of the insecticides priorto the administration of the formulation. Prior to administration, thepackages containing the two insecticides in their respective separatechambers are opened, and the two insecticides are dispensedsimultaneously or at least at about the same time, to the animal.

One way of providing the two components is to provide two containersthat each have flat bottoms and bulb shaped reservoirs in the top side.Each bulb can be in fluid communication with a channel portion extendingin a first direction from the reservoir. The two containers can bemirror images of each other, issued at a central connection save thatthey can be folded toward each other at the central connection, so thatthe two flat bottoms meet, leading to the forming of a familiar dropperbulb shape. The ends of the package, can be broken off to open the endsof the channels. Therefore, squeezing the bulb end will simultaneouslydispense both bulbs through both channels, onto the pet.

In yet another preferred embodiment of the invention, the insect growthregulator in the composition is pyriproxyfen or methoprene. Preferably,the insect growth regulator is packaged in the same chamber as eitherthe first insecticide or the second insecticide or in yet anothercontainer. Pyriproxyfen or methoprene are insecticides that act as aninsect growth inhibitor (IGR) by preventing flea eggs from hatching.

In another preferred embodiment of the invention, triphenyl phosphate(TPP) is added to the insecticide composition, preferably in an amountless than the insecticidally effective amount of the first and secondinsecticide in the composition. Triphenyl phosphate can be packaged inthe same container as either the first insecticide or the secondinsecticide. The selection of the chamber depends on the solvent inwhich the insecticide is solubilized.

Accordingly, it is an object of the invention to provide an improvedtopical insecticide composition that is highly effective against fleas,flea larvae, flea eggs, and ticks.

Another object of the invention is the provision of methods forcontrolling insect infestation.

Another object of the invention is to provide a topical insecticide thatworks more rapidly and/or more permanently than other insecticides.

Other objects and features will be in part apparent and in part pointedout.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the invention, insecticidal compositions, whichcontain a combination of insecticides and insect growth regulatorseffective to kill fleas and ticks, including flea eggs, flea larvae, andadult fleas and ticks, tick eggs, tick larvae and tick nymphs, areprovided. By selecting a combination of insecticides that are highlyeffective against fleas and combining them with insecticides that arehighly effective against ticks, the total amount of insecticide isoptimized. The combination of insecticides and insect growth regulatorsresult in insecticidal compositions having high insecticidal activityagainst fleas and ticks while allowing for a reduced amount of the totalvolume of insecticide required for application when compared tocompositions containing the individual insecticides alone. Compositionscontaining permethrin in accordance with the invention are particularlyadvantageous for use on dogs, compared to their use on cats.

The insecticidal compositions in accordance with the invention comprisea combination of a first insecticide component in an insecticidallyeffective amount to preferably achieve at least an 80% kill rate forfleas, a second insecticide component in an insecticidally effectiveamount to preferably achieve at least an 80% kill rate for ticks, and aninsecticidally effective amount of an insect growth regulator (IGR). Thecombination of the first and second insecticide components with aninsect growth regulator advantageously results in an insecticidalcomposition having a higher insecticidal activity against fleas, flealarvae, flea eggs and ticks compared to a composition containing eitherthe first or second insecticide or the insect growth regulator alone.

In a preferred embodiment of the invention, the first insecticidecomponent in the composition is in an insecticidally effective amount toachieve at least an 80% kill rate for fleas, more preferably at least a90% kill rate for fleas, even more preferably at least a 95% kill ratefor fleas, and most preferably, at least a 99% kill rate for fleas. Inanother preferred embodiment of the invention, the second insecticidecomponent in the composition is in an insecticidally effective amount toachieve at least an 80% kill rate for ticks, more preferably at least a90% kill rate for ticks, even more preferably, at least a 95% kill ratefor ticks, and most preferably, at least a 99% kill rate for ticks.

In one embodiment of the invention, the first and second insecticidecomponents in the composition are not the same insecticide and at leastone of the two insecticides in the composition is a pyrethrin or asynthetic pyrethroid. In other preferred embodiments of the invention,the first and second insecticide components in the composition are bothpyrethroids. It should of course be understood that additionalpyrethroids or non-pyrethroid insecticides can also be included.

In another embodiment of the invention, the first insecticide componentis a pyrethroid, and the second insecticide component is aneo-nicotinoid.

In one preferred embodiment of the invention, the first insecticidecomponent in the composition comprises a pyrethroid, preferablypermethrin. Other embodiments of the invention include cyphenothrinand/or fenpropathrin as the first insecticide component. The secondinsecticide component preferably comprises a neo-nicotinoid comprising a(tetrahydro-3-furanyl)methylamine derivative of following formula (1).The (tetrahydro-3-furanyl)methylamine derivatives of the formula (1)have an excellent insecticidal activity even in the absence of apyridylmethyl group or a thiazolylmethyl group in their molecularstructure.

where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ each represent each a hydrogen atomor an alkyl group having from 1 to 4 carbon atoms; R₁ represents ahydrogen atom, an alkyl group having from 1 to 5 carbon atoms, analkenyl group having 3 carbon atoms, a benzyl group, an alkoxyalkylgroup having from 2 to 4 carbon atoms (in its whole group), analkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms,an alkenylcarbonyl group having from 2 to 3 carbon atoms, acycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoylgroup, a benzoyl group substituted by alkyl group(s) having from 1 to 4carbon atoms, a benzoyl group substituted by halogen atom(s), a2-furanylcarbonyl group or an N,N-dimethylcarbamoyl group; R₂ representsa hydrogen atom, an amino group, a methyl group, an alkylamino grouphaving from 1 to 5 carbon atoms, a di-substituted alkylamino grouphaving from 2 to 5 carbon atoms (in its whole group), a 1-pyrrolidinylgroup, an alkenylamino group having 3 carbon atoms, an alkynylaminogroup having 3 carbon atoms, a methoxyamino group, an alkoxyalkylaminogroup having from 2 to 4 carbon atoms (in its whole group), a methylthiogroup or —N(Y₁)Y₁ (where Y₁ represents an alkyloxycarbonyl group havingfrom 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonylgroup having from 1 to 6 carbon atoms, an alkenylcarbonyl group havingfrom 2 to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6carbon atoms, a benzoyl group, a benzoyl group substituted by alkylgroup(s) having from 1 to 4 carbon atoms, a benzoyl group substituted byhalogen atom(s), a 2-furanylcarbonyl group, an N,N-dimethylcarbamoylgroup, a (tetrahydro-3-furanyl)methyl group or a benzyl group, and Y₂represents a hydrogen atom or an alkyl group having from 1 to 5 carbonatoms); and Z represents ═N—NO₂, ═CH—NO₂ or ═N—CN.

Intermediates for producing the compounds of the formula (1) arerepresented by a formula (2):

where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ each represent each a hydrogen atomor an alkyl group having from 1 to 4 carbon atoms; R₁₀ represents analkyl group having from 1 to 5 carbon atoms or a benzyl group; and R₁₁represents an alkyl group having from 1 to 5 carbon atoms or a benzylgroup.

The (tetrahydro-3-furanyl)methylamine derivatives of the formula (1) andformula (2) according to the invention are excellent compounds having ahigh insecticidal activity and broad insecticidal spectrum. Further,agricultural chemicals containing the (tetrahydro-3-furanyl)methylaminederivatives of formula (1) and (2) according to the invention haveoutstanding characteristics as insecticides and hence are useful.

Specific examples of the alkyl group for X₁, X₂, X₃, X₄, X₅, X₆ and X₇in the above formulae (1) and (2) include a methyl group, an ethylgroup, an n-propyl group, an iso-propyl group, a tert-butyl group, andthe like, preferably a methyl group.

Specific examples of the alkyl group for R₁ include a methyl group, anethyl group, an n-propyl group, an iso-propyl group, an n-butyl group,an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentylgroup, and the like.

Specific examples of the alkenyl group for R₁ include a 1-propenylgroup, a 2-propenyl group, and the like.

Specific examples of the alkoxyalkyl group for R₁ include amethoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, aniso-propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, andthe like.

Specific examples of the alkyloxycarbonyl group for R₁ include amethyloxycarbonyl group, an ethyloxycarbonyl group, ann-propyloxycarbonyl group, an iso-propyloxycarbonyl group, and the like.

Specific examples of the alkylcarbonyl group for R₁ include amethylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group,an iso-propylcarbonyl group, an n-butylcarbonyl group, aniso-butylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonylgroup, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and thelike.

Specific examples of the alkenylcarbonyl group for R₁ include avinylcarbonyl group, a 1-methylvinylcarbonyl group, and the like.

Specific examples of the cycloalkylcarbonyl group for R₁ include acyclopropylcarbonyl group, a cyclobutylcarbonyl group, acyclopentylcarbonyl group, a cyclohexylcarbonyl group, and the like.

Specific examples of the benzoyl group substituted by alkyl group(s) forR₁ include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and the like.

Specific examples of the benzoyl group substituted by halogen atom(s)for R₁ include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a4-chlorobenzoyl group, a 3,4-dichloro-benzoyl group, a 4-fluorobenzoylgroup, and the like.

Although R₁ can take various substituents as described above, it ispreferably a hydrogen atom, an alkylcarbonyl group having from 1 to 4carbon atoms or a cyclopropylcarbonyl group.

Specific examples of the alkylamino group for R₂ include a methylaminogroup, an ethylamino group, an n-propyl-amino group, an iso-propylaminogroup, an n-butylamino group, an iso-butylamino group, a sec-butylaminogroup, a tert-butylamino group, an n-pentylamino group, and the like,preferably a methylamino group.

Specific examples of the di-substituted alkylamino group for R₂ includea dimethylamino group, a diethylamino group, an N-methyl-N-ethylaminogroup, an N-methyl-N-n-propylamino group, an N-methyl-N-n-butylaminogroup, and the like, preferably a dimethylamino group.

Specific examples of the alkenylamino group for R₂ include a1-propenylamino group, a 2-propenylamino group, and the like.

Specific examples of the alkynylamino group for R₂ include apropargylamino group, and the like.

Specific examples of the alkoxyalkylamino group for R₂ include amethoxymethylamino group, an ethoxymethylamino group, ann-propoxymethylamino group, an iso-propoxymethylamino group, amethoxyethylamino group, an ethoxyethylamino group, and the like.

Specific examples of the alkyloxycarbonyl group denoted by Y₁ for R₂include a methyloxycarbonyl group, an ethyloxy-carbonyl group, ann-propyloxycarbonyl group, an iso-propyloxy-carbonyl group, and thelike.

Specific examples of the alkylcarbonyl group denoted by Y₁ for R₂include a methylcarbonyl group, an ethylcarbonyl group, ann-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonylgroup, an isobutylcarbonyl group, a sec-butyl-carbonyl group, atertbutylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonylgroup, and the like, preferably a methylcarbonyl group, an ethylcarbonylgroup, an n-propylcarbonyl group, an iso-propylcarbonyl group, ann-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonylgroup and a tert-butylcarbonyl group.

Specific examples of the alkenylcarbonyl group denoted by Y₁ for R₂include a vinylcarbonyl group, a 1-methyl-vinylcarbonyl group, and thelike.

Specific examples of the cycloalkylcarbonyl group denoted by Y₁ for R₂include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, acyclopentylcarbonyl group, a cyclo-hexylcarbonyl group, and the like,preferably a cyclopropyl-carbonyl group.

Specific examples of the benzoyl group substituted by alkyl group(s)denoted by Y₁ for R₂ include a 2-methylbenzoyl group, a 3-methylbenzoylgroup, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and thelike.

Specific examples of the benzoyl group substituted by halogen atom(s)denoted by Y₁ for R₂ include a 2-chlorobenzoyl group, a 3-chlorobenzoylgroup, a 4-chlorobenzoyl group, a 3,4-dichlorobenzoyl group, a 4-fluorobenzoyl group, and the like.

Specific examples of the alkyl group denoted by Y₁ for R₂ include amethyl group, an ethyl group, an n-propyl group, an iso-propyl group, ann-butyl group, an iso-butyl group, a sec-butyl group, a tert-butylgroup, an n-pentyl group, and the like, preferably a methyl group.

In the formula (1), compounds in which R₁ and Y₁ are concurrently analkylcarbonyl group having from 1 to 4 carbon atoms or acyclopropylcarbonyl group are preferred from the viewpoint of bothinsecticidal activity and production method.

It has been determined that the combination of two differentinsecticides and an insect growth regulator results in a compositionhaving high insecticidal activity when compared to compositionscontaining the first or second insecticide alone. Minimizing the amountof total insecticide administered to an animal is advantageous in orderto reduce concerns regarding toxicity of the insecticide to the animal,thereby providing for safer use. It is also useful to decrease transferof the insecticide onto humans, clothing and furniture. Therefore, thepresent invention allows for a lower amount of insecticide to beadministered to control insect infestation than would otherwise bepossible using the single insecticides alone.

In a preferred embodiment of the invention, the first insecticidecomponent in the composition comprises a pyrethroid and the secondinsecticide component comprises a neo-nicotinoid. In a preferredembodiment of the invention, the first insecticide component comprisescyclopropanecarboxylic acid, 3-(2,2-dichlorethenyl)-2,2-dimethyl-,(3-phenoxyphenyl)methyl ester (permethrin), and the second insecticidecomponent comprises1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran)or N-((6-chloro-3-pyridinyl)methyl)-N′-cyano-N-methyl-ethanimidanide(acetamiprid). Permethrin is an acaricide that will kill ticks, anddinotefuran and acetamiprid are insecticides that will kill adult fleas.In a preferred embodiment of the invention, the composition furthercontains an insect growth regulator, which is preferably pyriproxyfen ormethoprene.

In another preferred embodiment of the invention, the first insecticidecomponent in the composition comprises2,2-Dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid,(3-phenoxyphenyl)methyl ester (phenothrin), and the second insecticidecomponent comprises dinotefuran or acetamiprid.

Dinotefuran can be dissolved in particularly effective solvent systemssuch as a combination of water and ethanol or isopropanol, as disclosedin U.S. Pat. No. 6,814,030, incorporated by reference, or in phenylmethanol or ethanol, as disclosed in U.S. Pat. No. 6,588,374,incorporated by reference, or in ethyl lactate and water combinations.In a preferred embodiment of the invention, the composition furthercontains an insect growth regulator, which is preferably pyriproxyfen ormethoprene.

The insecticide compositions of the invention contain a combination ofinsecticides and insect growth regulators which are effective to killfleas, flea eggs, flea larvae, ticks, tick eggs, tick larvae and ticknymphs. The selection of the first insecticide component, the secondinsecticide component and insect growth regulator produces aninsecticide having high insecticidal activity. In a preferred embodimentof the invention, the first insecticide component or the secondinsecticide component is an acaricide, and even more preferred, thefirst insecticide component or the second insecticide component ispermethrin.

Of course, it should be understood that the insecticide composition maycontain one or more acaricides or other physiologically activeingredients. Additional acaricides that may be utilized in theinsecticide composition include but are not limited to, the followingclass of compounds: antibiotic acaricides (nikkomycins, thuringiensin);macrocyclic lactone acaricides (tetranactin); avermectin acaricides(abamectin, doramectin, eprinomectin, ivermectin, selamectin);milbemycin acaricides (milbemectin, milbemycin oxime, moxidectin);bridged diphenyl acaricides (azobenzene, benzoximate, benzyl benzoate,bromopropylate, chlorbenside, chlorfenethol, chlorfenson,chlorfensulphide, chlorobenzilate, chloropropylate, DDT, dicofol,diphenyl sulfone, dofenapyn, fenson, fentrifanil, fluorbenside,proclonol, tetradifon, tetrasul); carbamate acaricides (benomylcarbanolate, carbaryl, carbofuran, methiocarb, metolcarb, promacyl,propoxur); oxime carbamate acaricides (aldicarb, butocarboxim, oxamyl,thiocarboxime, thiofanox); dinitrophenol acaricides (binapacryl, dinex,dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinopenton,dinosulfon, dinoterbon, DNOC); formamidine acaricides (amitrazchlordimeform, chloromebuform, formetanate, formparanate); mite growthregulators (clofentezine, dofenapyn, fluazuron, flubenzimine,flucycloxuron, flufenoxuron, hexythiazox); organochlorine acaricides(bromocyclen, camphechlor, DDT, dienochlor, endosulfan, lindane);organophosphorus acaricides (chlorfenvinphos, crotoxyphos, dichlorvos,heptenophos, mevinphos, monocrotophos, naled, schradan, TEPP,tetrachlorvinphos); organothiophosphate acaricides (amidithion, amiton,azinphos-ethyl, azinphos-methyl, azothoate, benoxafos, bromophos,bromophos-ethyl, carbophenothion, chlorpyrifos, chlorthiophos,coumaphos, cyanthoate, demeton, demeton-O, demeton-S, demeton-methyl,demeton-O-methyl, demeton-5-methyl, demeton-5-methylsulphon, dialifos,diazinon, dimethoate, dioxathion, disulfoton, endothion, ethion,ethoate-methyl, formothion, malathion, mecarbam, methacrifos, omethoate,oxydeprofos, oxydisulfoton, parathion, phenkapton, phorate, phosalone,phosmet, phoxim, pirimiphos-methyl, prothidathion, prothoate,pyrimitate, quinalphos, quintiofos, sophamide, sulfotep, thiometon,triazophos, trifenofos, vamidothion); phosphonate acaricides(trichlorfon); phosphoramidothioate acaricides (isocarbophos,methamidophos, propetanphos); phosphorodiamide acaricides (dimefox,mipafox); organotin acaricides (azocyclotin, cyhexatin, fenbutatinoxide); phenylsulfamide acaricides (dichlofluanid); phthalimideacaricides (dialifos, phosmet); pyrazole acaricides (acetoprole,fipronil, tebufenpyrad, vaniliprole); pyrethroid acarcides such aspyrethroid ester acaricides (acrinathrin, bifenthrin, cyhalothrin,cypermethrin, alpha-cypermethrin, fenpropathrin, fenvalerate,flucythrinate, flumethrin, fluvalinate, tau-fluvalinate, permethrin) andpyrethroid ether acaricides (halfenprox); pyrimidinamine acaricides(pyrimidifen); pyrrole acaricides (chlorfenapyr); quinoxaline acaricides(chinomethionat, thioquinox); sulfite ester acaricides (propargite);tetronic acid acaricides (spirodiclofen); thiocarbamate acaricides(fenothiocarb); thiourea acaricides (chloromethiuron, diafenthiuron);and other unclassified acaricides (acequinocyl, amidoflumet, arsenousoxide, bifenazate, closantel, crotamiton, disulfuram, etoxazole,fenazaflor, fenazaquin, fenpyroximate, fluacrypyrim, fluenetil,mesulfen, MNAF, nifluridide, pyridaben, sulfuram, sulfluramid, sulfur,triarathene).

Other acaricides or other physiologically active substances that may beutilized in the insecticide composition of the present invention areacephate, Bacillus thuringiensin aizawai, Bacillus thuringiensiskurstaki, Beauveria bassiana, Bendiocarb, Bifenthrin, Carbaryl,Chlopyrifos+DDVP, Chlorpyrifos+pyrethrin, Cyfluthrin, Ethoprop,Fenamiphos, Fenoxycarb, Fipronil, Fonofos, Halofenozide, Heterorhabditisbacteriophora, Hydramethylnon, Imidacloprid, Isofenphos,Lambda-cyhalothrin, Lindane, Malathion, Myrothecium verrucaria,Permethrin, Spinosad, and Trichlorfon, Acequinocyl, Acetamiprid,Acibenzolar-S-Methyl, Azoxystrobin, Boscalid, Bromuconazole,Carfentrazone-ethyl, Clodinafop-Propargyl, Clofencet,Cloransulam-methyl, Clothianidin, Copper Octanoate, Cuprous Chloride,Cyclanilide, Cyhalofop-butyl, Cymoxanil, Cyprodinil, Diclosulam,Diflufenzopyr, Dimethomorph, Ecolyst, Etoxazole, Fenhexamid, Fluazinam,Flufenacet, Flumioxazin, Fluoroxypyr, Fluthiacet-Methyl, Famoxadone,Foramsulfuron, Imazamox, Imiprothrin, Indoxacarb, Isoxaflutole,Kresoxim-methyl, Lithium Perfluorooctane Sulfonate (LPOS), Mesotrione,N-Methylneodecanamide, Novaluron, Phosphine, Pirimicarb, ProhexadioneCalcium, Propazine, Pymetrozine, Spinosad, Sulfentrazone, Tebufenpyrad,Thiacloprid, Thiazopyr, Tolylfluanid, Tralkoxydim, Trifloxystrobin,Zoxamide, Amitraz, chrorpyrifos, chrorpyrifos plus cypermethrin,chrorpyrifos plus dizinon, chrorpyrifos plus permethrin, coumaphos,crotozyphos plus dichlorvos, cyfluthrin, cypermethrin, diazinon,dichlorvos, dichlorvos plus pyrethrins, dichlorvos plustetrachlorvinphos, dimethoate, doramectin, eprinomectin, ethion,famphur, fenthion, fenvalerate, ivermectin, lambda-cyhalothrin,lambda-cyhalothrin plus pirimiphos methyl, lindane, malathion, malathionplus methoxychlor, malathion plus sulphur, methomyl, methoxychlor,methoxychlor plus pyrethrins, moxidectin, naled, nithiazine, permethrinplus pyrethrins, phosmet, pirimiphos methyl, and pyrethrins.

It has been determined that it is difficult to form a high concentrationof dinotefuran and permethrin or phenothrin and it is likely to resultin a solution that can be unstable when stored at tempuraters generallyencountered by insecticides between the time they are manufactured andwhen they are used for reasonable amounts of time. Accordingly, it ispreferable that these two insecticides are packaged in a containerhaving two associated, preferably attached, but individual chambers toprevent the mixing of the insecticides prior to the administration ofthe formulation. Prior to administration, the container can be openedand the two insecticides can be dispensed simultaneously or nearlysimultaneously, to the companion animal. In one embodiment of theinvention, the package is constructed so that both chambers can bedispensed at once.

In another embodiment of the invention, one of the active ingredients,for example, dinotefuran or permethrin, can be encapsulated or containedin micelles or lipids in the formulation. In this embodiment of theinvention, topical formulations can be packaged and stored in a singlecontainer prior to administration to the animal.

In a preferred embodiment of the invention, the insecticide compositionof the invention is packaged in a single dose package. Single dosecontainers make storage and disposal more convenient for animal owners.Preferably, the insecticide composition is packaged in a container,encompassing two associated, preferably attached but individualchambers, which are separated by a barrier, preferably plastic, plasticcoated paper or metal, such as aluminum foil. In one embodiment of theinvention, the first chamber, and the second chamber, are plastic tubesthat are separate but fused together. During packaging, the firstinsecticide, preferably permethrin or phenothrin, is placed in the firstchamber and the second insecticide, preferably dinotefuran oracetamiprid, is placed in the second chamber. Preferably, the first andsecond chambers are separated by a barrier that prevents the interactionof the first and second insecticides. In another preferred embodiment ofthe invention, an insect growth regulator, preferably methoprene orpyriproxyfen, is added to the insecticide composition and placed in thesame chamber with either the first insecticide or the second insecticideor even separately in yet another container.

The entire container containing the two insecticides in separatechambers is sealed, preferably with a tab or top, for use in opening thecontainer prior to administration. After the container is sealed, theinsecticide formulation can be safely stored in the container untiladministration of the insecticide formulation to the animal.

Prior to administration of the insecticide formulation to the animal,the container is opened by removing the tab or top. In one embodiment ofthe invention, the container is opened by twisting the tab therebyresulting in breaking or tearing of the barrier separating the twochambers, thereby allowing the two insecticides, preferably permethrinand dinotefuran, to mix prior to administration of the insecticideformulation to the animal. After the two insecticides are mixed, the twoinsecticides are dispensed simultaneously by squeezing or collapsing thebody of the individual containers. In another embodiment of theinvention, the two are not combined until they are dispensed onto theanimal. A dual plunger system can also be employed to administer theformulation to the animal.

It is of course understood that the two insecticides need not be mixedtogether prior to administration of the insecticide formulation to theanimal. Accordingly, in another embodiment of the invention, opening ofthe dual-chamber container does not result in the mixing of the twoinsecticides. After the container is opened, the two insecticides aredispensed onto the animal by squeezing or collapsing the container orcontainers, either simultaneously or sequentially.

In one embodiment of the invention, the composition is packaged withinstructions, advising to mix the insecticides. In other embodiments ofthe invention, the instructions will direct the user to mix theinsecticides upon application. In one embodiment of the invention, acontainer is provided with multiple single dose packages therein.

Because compositions in accordance with preferred embodiments of theinvention have a high concentration of insecticide, a relatively smallapplication of a spot or line on the animal can effectively prevent andcontrol flea and tick infestation on the animal for up to four weekspost-administration. Preferably, the insecticide formulation isnon-toxic and does not irritate the animal's skin. Applications aretypically in the range of 0.5 to 10 ml. In certain embodiments of theinvention, the compositions are applied in the range of about 0.05 to0.5 ml/kg of animal body weight.

In one preferred embodiment of the invention, the insecticidecomposition comprises permethrin in a concentration range of about 40 to65%, dinotefuran in a concentration range of about 5 to 15%, andpyriproxyfen or methoprene in a concentration range of about 1 to 3%. Inanother preferred embodiment of the invention, the insecticidecomposition comprises permethrin in a concentration range of about 40 to65%, dinotefuran in a concentration range of about 5 to 20%, andpyriproxyfen or methoprene in a concentration range of about 1 to 3%.All percentages, unless otherwise specified, are on a weight basis.

While an effective dosage of the insecticide composition needs to beapplied to the animal for optimum effectiveness against fleas, fleaeggs, flea larvae and ticks, the active dosages of the first insecticideand second insecticide depend upon the size of the animal. Compositionscontaining permethrin are particularly advantageous for use on dogs,compared to their use on cats.

Preferably, up to 4 ml of insecticide may be administered to a dogweighing 89-140 pounds. Such composition will preferably contain atleast about 1300 to 2600 mg permethrin, at least about 300 mgdinotefuran, and at least about 20 mg of pyriproxyfen.

Preferably, up to 3 ml of insecticide may be administered to a dogweighing 45 to 88 pounds. Such composition will preferably contain atleast about 910 to 1800 mg permethrin, at least about 240 mgdinotefuran, and at least about 16 mg of pyriproxyfen.

Preferably, up to 2.1 ml of insecticide may be administered to a dogweighing 23 to 44 pounds. Such composition will preferably contain atleast about 455 to 1300 mg permethrin, at least about 210 mgdinotefuran, and at least about 14 mg of pyriproxyfen.

Preferably, up to 1.5 ml of insecticide may be administered to a dogweighing 22 pounds or less. Such composition will preferably contain atleast about 175 to 650 mg permethrin, at least about 150 mg dinotefuran,and at least about 10 mg of pyriproxyfen.

In another preferred embodiment of the invention, the insecticidecomposition comprises phenothrin, dinotefuran and pyriproxyfen.Insecticide compositions containing phenothrin in accordance with theinvention are particularly advantageous for use on both dogs and cats.Preferably, the insecticide composition comprises phenothrin in aconcentration range of between 80 to 87%, more preferably approximately85.7%, dinotefuran in a concentration range of 5 to 15%, andpyriproxyfen or methoprene in a concentration range of 1 to 2%. Inanother preferred embodiment of the invention, the insecticidecomposition comprises phenothrin in a concentration range of about 80 to87%, more preferably approximately 85.7%, dinotefuran in a concentrationrange of about 5 to 20%, and pyriproxyfen or methoprene in aconcentration range of about 1 to 3%. All percentages, unless otherspecified, are on a weight basis.

The actual amount of the active dosage of the active ingredient willvary depending on the size of the dog or cat. Effective dosages includethe following on a mg active ingredient per kg animal body weight basis.See Table 1.

TABLE 1 Pyriproxyfen Weight of Dog Permethrin (mg/kg) Dinotefuran(mg/kg) (mg/kg) 10 lbs or less >61 >8.9 >0.89 (4.5 kg or less) 11-20 lbs60-108 8.9-16.1 0.89-1.61 (5-9.1 kg) 21-55 lbs 50-126 6.6-17.0 0.66-1.70(9.5-25 kg) >55 lbs <70 <7.8 <0.78 (>25 kg)

Another embodiment of the invention provides for a method forcontrolling insect infestation in a dog comprising administering about15 to 130 mg/kg dog body weight of permethrin, 1.5 to 20 mg/kg dog bodyweight of dinotefuran and 0.15 to 2 mg/kg dog body weight ofpyriproxyfen. In yet another embodiment of the invention the methodcomprises administering about 80 to 500 mg/kg dog body weight ofphenothrin, 1.5 to 20 mg/kg dog body weight of dinotefuran and 0.15 to 2mg/kg dog body weight of pyriproxyfen. In another embodiment of theinvention the method comprises administering about 15 to 130 mg/kg dogbody weight of permethrin, 0.5 to 20 mg/kg dog body weight ofacetamiprid and 0.15 to 2 mg/kg dog body weight of pyriproxyfen. In yetanother embodiment of the invention the method comprises administeringabout 80 to 500 mg/kg dog body weight of phenothrin, 0.5 to 20 mg/kg dogbody weight of acetamiprid and 0.15 to 2 mg/kg dog body weight ofpyriproxyfen.

Another embodiment of the invention provides a method for controllinginsect infestation in a cat comprising administering about 100 to 1000mg/kg cat body weight of phenothrin, 15 to 180 mg/kg cat body weight ofdinotefuran and 2 to 18 mg/kg cat body weight of pyriproxyfen. In yetanother embodiment of the invention the method comprises administeringabout 100 to 1000 mg/kg cat body weight of phenothrin, 3 to 200 mg/kgcat body weight of acetamiprid and 2 to 18 mg/kg cat body weight ofpyriproxyfen.

It should be noted that in embodiments where the formulation is packagedusing separate chambers or containers, the percentage of an activeingredient provided is the percentage of that active ingredient in asingle solution. For example, 1 to 2% pyriproxyfen is the concentrationof pyriproxyfen contained in the formulation in a single chamber ratherthan the concentration of pyriproxyfen in the total formulation of thecombined chambers.

For use on cats, up to 1.1 ml of total insecticide may preferably beadministered to a cat weighing less than 10 pounds and up to 1.5 ml ofinsecticide may be administered to a cat weighing 10 pounds or more.Preferably, the volume of phenothrin being administered to a cat isbetween about 0.25 to 0.85 ml for a cat weighing less than 10 pounds andbetween about 0.35 and 1.25 ml for a cat weighing 10 pounds or more. Avolume of 1.0 ml and 1.3 ml, respectively, for a phenothrin containingproduct is preferred.

Insecticide compositions containing phenothrin are also particularlyeffective for use on dogs. Preferably, approximately up to 1.5 ml oftotal insecticide may be administered to a dog weighing under 30 pounds,approximately up to 3.0 ml of total insecticide may be administered to adog weighing less than 45 pounds, approximately up to 4.1 ml of totalinsecticide may be administered to a dog weighing 41-60 pounds,approximately up to 4.6 ml of total insecticide may be administered to adog weighing 61-90 pounds, and approximately up to 6.0 ml of totalinsecticide may be administered to a dog weighing over 90 pounds.Preferably, the amount of phenothrin in the insecticide composition isbetween 0.3 to 0.9 ml for a dog weighing 4 to 15 pounds, between about0.25 to 0.85 ml for a dog weighing 16 to 30 pounds, between about 0.65to 1.95 ml for a dog weighing 31 to 45 pounds, between about 1.0 to 3.0ml for a dog weighing 46 to 60 pounds, between about 1.15 to 3.45 ml fora dog weighing 61 to 90 pounds, and between about 1.5 to 4.5 ml for adog weighing more than 90 pounds.

In another preferred embodiment of the invention, the insecticidecomposition comprises permethrin, acetamiprid and pyriproxyfen.Preferably, the insecticide composition comprises permethrin in aconcentration range of 45 to 65%, acetamiprid in a concentration rangeof 5 to 50%, and pyriproxyfen in a concentration range of 0.5 to 5%. Inyet another preferred embodiment of the invention, the insecticidecomposition comprises permethrin in a concentration range of about 40 to65%, acetamiprid in a concentration range of about 5 to 50%, andpyriproxyfen in a concentration range of about 0.5 to 5%.

In another preferred embodiment of the invention, the insecticidecomposition comprises phenothrin, acetamiprid and pyriproxyfen.Preferably, the insecticide composition comprises phenothrin in aconcentration range of 5 to 90%, acetamiprid in a concentration range of5 to 50%, and pyriproxyfen in a concentration range of 0.5 to 5%.

Preferably, the insecticidal compositions of the present inventionfurther comprises an enzyme inhibitor or a synergist such as piperonylbutoxide, N-octylbicycloheptenedicarboximide, triphenyl phosphate, whichpreferably increases the efficacy of the composition. Preferably, theinsecticidal compositions also contain one or more compounds to increasethe efficacy and to reduce the irritation of pyrethroid insecticides tothe skin of animals.

In a preferred embodiment, the insecticidal compositions furthercomprise an effective amount of triphenyl phosphate (TPP) to increaseefficacy, typically less than the amount of active ingredient. Theamount of TPP to include in the composition relative to theconcentration of the first and second insecticide component in thecomposition can be readily determined using routine experimentation todetermine the optimum synergistic effect.

In the preparation of a formulation for use on animals, there areseveral parameters that should be considered. These are:

-   -   Concentration high enough to minimize the volume of the topical        applied to the animal (one would not want to put 20 ml, e.g.,        onto a small dog).    -   Concentration low enough to achieve effective translocation of        the topical insecticide over the animal's skin.    -   The formulation should be stable for one month at 130° F., 110°        F., 40° F., room temperature and 0° F. This helps ensure that        the formulation remains stable under the conditions that it        could meet in commerce.    -   Safe to use on the intended animal—particularly non-irritating        to at least the intended animal, since the product is applied to        the skin. Also safe if ingested by the animal; ingestion can        occur when pets groom themselves.    -   Safe to use by the consumer.    -   Efficacious in use—should kill greater than 90% of the fleas and        ticks up to 28 days.    -   Efficacy would be reduced if crystallization occurred in the        package.    -   Needs to be aesthetically pleasing—“no oily drop” on the animal        when applied.    -   Fast drying to reduce the chance of the animal shaking off the        liquid thereby reducing efficacy.    -   Microbiologically stable.

Other additives to the insecticidal composition include but are notlimited to fragrances, surfactants and spreading agents to increaseperformance such as polysorbate 20 and polysorbate 80, and isopropylmyristate. Polymers such as agar, gelatin, alginate, and cationicpolymers such as cationic agar, cationic cellulose, cationic acrylates,and polyoxymethylene urea may also be added to provide enrobing of theinsecticide to improve safety and adhesion to skin and hair.

Solvent Containing N-octyl Pyrrolidone and/or N-methylpyrrolidone

In accordance with another preferred embodiment of the invention, theinsecticide composition includes N-octyl pyrrolidone (NOP) and/orN-methylpyrrolidone (NMP) in the solvent. Preferably, the firstinsecticide component comprises permethrin and the second insecticidecomponent comprises dinotefuran. The inventors determined that N-octylpyrrolidone and N-methylpyrrolidone, either alone or in combination, canincrease the degree of dissolution of the insecticide components, morespecifically, permethrin and dinotefuran. The greater amount ofdissolution can enhance efficiency of the insecticide composition byrequiring less solvent to dissolve the same amount of insecticidecompositions. This leads to greater concentrations of insecticide.

Preferably, the insecticide composition comprises N-octyl pyrrolidone ina concentration range of approximately 0-10%, more preferably about5-7%, most preferably approximately 6%. Additionally, the insecticidecomposition can comprise N-methyl pyrrolidone in a concentration rangeof approximately 40-60%. Preferably, the insecticide compositioncomprises permethrin in a concentration range of between approximately35 to 50%, more preferably approximately 37%, dinotefuran in aconcentration range of approximately 0 to 10%, and pyriproxyfen in aconcentration range of approximately 0 to 5%. All percentages, unlessother specified, are on a weight basis.

Formulation A: In one exemplary embodiment of the invention, theinsecticide composition comprises permethrin in a concentration of about37%, dinotefuran in an amount of about 5%, pyriproxyfen in aconcentration of about 0.45%, N-octyl pyrrolidone in a concentrationrange of approximately 0-6% and N-methylpyrrolidone in a concentrationrange of approximately 51-57%. All percentages, unless otherwisespecified, are on a weight basis.

Formulation B: In one exemplary embodiment of the invention, theinsecticide composition comprises permethrin in a concentration of about37.08%, dinotefuran in a concentration range of about 7.5-10%,pyriproxyfen in a concentration range of about 1-5%, N-octyl pyrrolidonein a concentration range of approximately 0-6%, preferably about 6% andN-methylpyrrolidone in a concentration range of approximately 41-55%.All percentages, unless otherwise specified, are on a weight basis.

Formulation C: In one exemplary embodiment of the invention, theinsecticide composition comprises permethrin in a concentration of about47.97%, N-octyl pyrrolidone in a concentration range of approximately4-6% and ethyl lactate in a concentration range of approximately48.03-50.03%. All percentages, unless otherwise specified, are on aweight basis.

Formulation D: In one exemplary embodiment of the invention, theinsecticide composition comprises permethrin in a concentration of about37.08%, dinotefuran in a concentration of about 5%, pyriproxyfen in aconcentration range of about 1-5%, N-octyl pyrrolidone in aconcentration range of approximately 0-6%, preferably about 6%, andN-methyl pyrrolidone in a concentration range of approximately 46-57%.All percentages, unless otherwise specified, are on a weight basis.

Formulation E: In one exemplary embodiment of the invention, theinsecticide composition comprises a first tube having permethrin in aconcentration of about 45%, N-octyl pyrrolidone in a concentration ofapproximately 6% and ethyl lactate in a concentration range ofapproximately 49%. All percentages, unless otherwise specified, are on aweight basis.

Formulation F: In one exemplary embodiment of the invention, theinsecticide composition comprises a first chamber having permethrin in aconcentration range of about 32-48% and ethyl lactate in a concentrationrange of about 52-58% and a second chamber having dinotefuran at aconcentration range of about 10-20%, pyriproxyfen at a concentration ofabout 0.25-5.0%, N-octyl pyrrolidone at a concentration of about0.15-0.5% and ethyl lactate at a concentration of about 43-51%.

Formulation G: In one exemplary embodiment of the invention, theinsecticide composition comprises a first chamber having permethrin in aconcentration range of about 46% and ethyl lactate in a concentrationrange of about 54% and a second chamber having dinotefuran at aconcentration range of about 15%, pyriproxyfen at a concentration ofabout 1.5%, N-octyl pyrrolidone at a concentration of about 0.2% andethyl lactate at a concentration of about 48%.

It will be readily appreciated by the skilled artisan that theformulations described herein may also comprise additives including, butnot limited to, fragrances, hair conditioners, solvation aids, spreadingagents, solubilizers and UV protectants.

The formulation can be applied as a topical drop about once per month,preferably in the area between the shoulder blades and the base of theskull to kill fleas and flea eggs for over a one month period. In theembodiments of the present invention described herein, up to 20 ml ofthe formulation can be applied to the animal, with about 1.0 ml being amore typical application to kill fleas and flea eggs for over a onemonth period. In certain embodiments of the invention, as application ofabout 0.4 ml can be sufficient to kill fleas and flea eggs for over aone month period.

In practice, an effective amount of the insecticidal compositions asdescribed herein may be applied to a companion animal, preferably a dog,as a foaming shampoo, dip, aerosol spray, pump spray, powder, lotion,emulsifiable concentrate, aqueous or liquid flowable, suspensionconcentrate and by any other methods suitable for administering topicalcompositions to animals.

The preparations are suitable for combating insect infestations whichoccur in animal husbandry and animal breeding in productive, breeding,zoo, laboratory, experimental animals and pets, and have a favorabletoxicity to warm-blooded animals. Productive and breeding animalsinclude mammals, such as, for example, cattle, horses, sheep, pigs,goats, camels, water buffalo, donkeys, rabbits, fallow deer andreindeer, and pelt animals, such as, for example, mink, chinchilla andraccoons.

Laboratory and experimental animals include mice, rats, guinea pigs,hamsters, dogs and cats.

Pets include dogs and cats and many of the laboratory and experimentalanimals.

The formulation according to the invention is particularly preferablyadministered to companion animals such as dogs and cats, but can besuitable for other mammals.

The following examples are given for purposes of illustration only andare not intended to be construed in a limiting manner.

EXAMPLES Example 1 Preparation of1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran)

A mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol, 29.5 g oftrifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml ofdichloromethane was stirred for an hour at room temperature. Water waspoured into the reaction solution to separate the organic layer, whichwas washed with 1 N hydrochloric acid, water and a saturated salinesolution, dried, and concentrated to obtain 20 g of3-tetrahydro-furanylmethyl triflate. 3.25 g of 60% sodium hydride wereadded to 12.5 g of 1,5-dimethyl-2-nitroiminohexahydro-1,3,5-triazine and60 ml of DMF at room temperature, followed by stirring for an hour. 20.0g of the 3-tetrahydrofuranylmethyl triflate were added thereto, and themixture was stirred at 50° C. for 2 hours. After cooling the mixture toroom temperature, 50 ml of 2N hydrochloric acid were added thereto,followed by stirring at 50° C. for 2 hours. The resultant mixture wasneutralized with sodium bicarbonate and extracted with dichloromethane,and the extract was dried and concentrated. The residue thus obtainedwas purified by silica gel column chromatography (eluent: 1:1 ratio ofethyl acetate/hexane) to obtain 7.8 g of1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran).

Example 2 Preparation of Insecticide Formulation Containing Dinotefuranand Pyriproxyfen

25 g of dinotefuran was added to 100 ml phenyl methanol with stirringuntil it dissolved. 1 g of pyriproxyfen was added to the solution withstirring to produce a clear, homogeneous solution of high insecticideconcentration.

The resulting solution can be spot applied to companion animals, such asdogs and will kill fleas, ticks and other insects.

Example 3 Preparation of Insecticide Formulation Containing Permethrin,Dinotefuran and Pyriproxyfen

Permethrin (65 g) was added to a clean container. Safflower oil (35 g)was added with stirring until the solution was homogeneous. Thissolution containing permethrin and safflower oil was added to one of thechambers in the package in the appropriate volume based on the dosagerequired.

Pyriproxyfen (1 g) and Mackernium KP (1 g) were added to a cleancontainer, and gently heated until the pyriproxyfen liquefied. Water(27.6 g) was added with stirring, followed by the addition of ethyllactate (55.4 g). Dinotefuran (15 g) was added and the solution wasmixed and heated at 50° C. until the dinotefuran dissolved. The solutionwas cooled to room temperature and the pH adjusted to 5.5 by theaddition of sodium carbonate (0.15 g of a 25% aqueous solution). Thissolution was added to the other chamber in the package in theappropriate volume based on the dosage required.

Example 4 Stability of Permethrin/Dinotefuran/Pyriproxfen Formulation

Compositions containing dinotefuran and pyriproxyfen prepared accordingto the methodology of Example 3 are stable for at least 1 month at 130°F., 3 months at 110° F., 1 month at 40° F. and 1 month at room temp.(approx. 70° F.). The stability of the formulation is based on thecriterion of no crystal formation during a 1 month period.

Example 5 Preparation of Insecticide Formulation Containing Permethrin,Acetamiprid and Pyriproxyfen

10 grams acetamiprid was added to 89 grams ethanol and stirred until theacetamiprid dissolved. 1 gram of pyriproxyfen was added to this solutionand stirred until it dissolved. This solution was added to theappropriate chamber in the dual chamber package.

Example 6 Preparation of Insecticide Formulation Containing Permethrin,Dinotefuran and Pyriproxyfen

Formulation 1:

A solution was prepared containing 55% ethyl lactate (CAS # 97-64-3) and45% permethrin (CAS # 52645-53-1). Variation of up to ±10% can beacceptable. The permethrin may be stored at slightly below roomtemperature in a solid state. If solid, then the permethrin/ethyllactate solution is heated slightly with moderate mixing. The meltingpoint of permethrin is 20-23° C.

Formulation 2:

The following materials were added to the mixture to a finalconcentration of the indicated percentages by weight.

TABLE 2 Ingredient CAS # % w/w Pyriproxyfen (Sumilarv 95737-68-1 1.50 (±1.0 variation Technical Grade) acceptable) Polyvinylpyrrolidone-vinyl25086-89-9 1.50 (± 0.5 variation acetate copolymer (50% acceptable)solution in water) (PVP/VA W-375 copolymer) Glycerol-polyethylene glycol61788-85-0 7.50 (± 1.0 variation oxystearate (hydrogenated) acceptable)castor oil Sodium bis(2- 577-11-7 1.00 (± 0.3 variationethylhexyl)sulfoxuccinate acceptable) (75% solution in water) Vitamin Eacetate 58-95-7 2.50 (± 0.7 variation acceptable) 1-octyl-2-pyrrolidone2687-94-7 0.20 (± 0.2 variation acceptable) Lactic acid, ethyl ester97-64-3 47.80 (± 10.0 variation acceptable) Water (buffered) LocalSource 22.00 (± 10.0 variation acceptable) Dinotefuran 165252-70-0 15.00(± 2.0 variation acceptable) Citric Acid, trisodium salt 68-04-2 0.11 (±0.6 variation acceptable) Citric Acid 77-92-9 0.01 (± 0.005 variationacceptable) Total 100.00

In a separate vessel, 0.2M citric acid and 0.2 M sodium citrate buffersolution was prepared and set aside.

To a clean beaker, pyriproxyfen (15 gm) and olealkonium chloride (10 gm)was added. The solution was heated to 50° C. and mixed moderately untilhomogeneous. Note that there is no need to heat if pyriproxyfen is inliquid form. Glycerol polyethylene glycol oxystearate (hydrogenated)castor oil (75 gm), Vitamin E acetate (25 gm), PVP/VA W-735 copolymer(15 gm), sodium dioctyl sulfosuccinate (10 gm) were added withcontinuous mixing. The mixing speed was increased as the viscosityincreased.

When the solution became homogeneous, ethyl lactate (478 gm) was addedand the mixing speed was adjusted accordingly. 220 gm of the set asidebuffered solution was then added and then the dinotefuran (150 gm). Thesolution was heated to 40° C. until the dinotefuran fully dissolved.Then the n-octyl pyrrolidone (2 gm) was added. The solution was cooledoff and the pH was measured (pH range=5.5-7.0).

For application to the animal the formulations can be stored in a dualchamber package (delivery system) that allows simultaneous delivery ofboth formulations to the skin of the animal. The volume of Formulation 1can range from 0.5-6 ml, and the volume of Formulation 2 can range from0.5-3 ml dependent on the size (weight) of the animal.

Example 7 Stability of Formulations B, C and D

The following examples of the insecticide composition in accordance withthe embodiment of Formulations B, C and D were tested for color,appearance and uniformity in various temperatures, some over theduration of four days. The composition of these examples and the testresults are provided below. The following examples are given forpurposes of illustration only and are not intended to be construed in alimiting manner:

Sample Compositions:

FORMULATION B: (% concentration) Composition Numbers Ingredients3061-59A 3061-59B 3061-59C 3061-59D 3061-59E 3061-59F Permethrin 37.0837.08 37.08 37.08 37.08 37.08 S-1638 7.50 7.50 7.50 7.50 7.50 7.50Agsolex 8 — — — 6.00 6.00 6.00 Nylar 1.00 2.50 5.00 1.00 2.50 5.00n-Methyl pyrrolidone 54.42 52.92 50.42 48.42 46.92 44.42 CompositionNumbers Ingredients 3061-59G 3061-59H 3061-59I 3061-59J 3061-59K3061-59L Permethrin 37.08 37.08 37.08 37.08 37.08 37.08 S-1638 10.0010.00 10.00 10.00 10.00 10.00 Agsolex 8 — — — 6.00 6.00 6.00 Nylar 1.002.50 5.00 1.00 2.50 5.00 n-Methyl pyrrolidone 51.92 50.42 47.92 45.9244.42 41.92 FORMULATION C: (% concentration) Composition NumbersIngredients 3061-61A 3061-61B Ethyl lactate 50.03 48.03 Permethrin 45.9745.97 Agsolex 8 4.00 6.00 TS# 12838 FORMULATION D: (% concentration)Composition Numbers Ingredients 3061-64A 3061-64B 3061-64C 3061-64D3061-64E 3061-64F Permethrin 37.08 37.08 37.08 37.08 37.08 37.08 S-16385.00 5.00 5.00 5.00 5.00 5.00 Agsolex 8 — — — 6.00 6.00 6.00 Nylar 1.002.50 5.00 1.00 2.50 5.00 n-Methyl pyrrolidone 56.92 55.42 52.92 50.9249.42 46.92

S-1638 is dinotefuran and Agsolex 8 is N-octyl pyrrolidone. Pyriproxyfenis also known as Nylar.

Test Results:

Table 3 shows the results of the stability testing at room temperature,4° C. and under freeze (0° F.)/thaw conditions.

TABLE 3 Room Temperature 4° C. R/T INITIAL Day 4 INITIAL Day 4 INITIALDay 4 Comp # 3061-59A Color sl yellow sl yellow sl yellow sl yellow slyellow sl yellow Appearance clear clear clear clear clear clear Uniform?yes yes yes yes yes yes Comp # 3061-59B Color sl yellow sl yellow slyellow sl yellow sl yellow sl yellow Appearance clear clear clear clearclear clear Uniform? yes yes yes yes yes yes Comp # 3061-59C Color slyellow sl yellow sl yellow sl yellow sl yellow sl yellow Appearanceclear clear clear clear clear clear Uniform? yes yes yes yes yes yesComp # 3061-59D Color sl yellow sl yellow sl yellow sl yellow sl yellowsl yellow Appearance clear clear clear clear clear clear Uniform? yesyes yes yes yes yes Comp # 3061-59E Color sl yellow sl yellow sl yellowsl yellow sl yellow sl yellow Appearance clear clear clear clear clearclear Uniform? yes yes yes yes yes yes Comp # 3061-59F Color sl yellowsl yellow sl yellow sl yellow sl yellow sl yellow Appearance clear clearclear clear clear clear Uniform? yes yes yes yes yes yes Comp # 3061-59GColor sl yellow sl yellow sl yellow Appearance clear clear clearUniform? yes yes yes Comp # 3061-59H Color sl yellow sl yellow sl yellowAppearance clear clear clear Uniform? yes yes yes Comp # 3061-59I Colorsl yellow sl yellow sl yellow Appearance clear clear clear Uniform? yesyes yes Comp # 3061-59J Color sl yellow sl yellow sl yellow Appearanceclear clear clear Uniform? yes yes yes Comp # 3061-59K Color sl yellowsl yellow sl yellow Appearance clear clear clear Uniform? yes yes yesComp # 3061-59L Color sl yellow sl yellow sl yellow Appearance clearclear clear Uniform? yes yes yes Comp # 3061-64A Color sl yellow slyellow sl yellow Appearance clear clear clear Uniform? yes yes yes Comp# 3061-64B Color sl yellow sl yellow sl yellow Appearance clear clearclear Uniform? yes yes yes Comp # 3061-64C Color sl yellow sl yellow slyellow Appearance clear clear clear Uniform? yes yes yes Comp # 3061-64DColor sl yellow sl yellow sl yellow Appearance clear clear clearUniform? yes yes yes Comp # 3061-64E Color sl yellow sl yellow sl yellowAppearance clear clear clear Uniform? yes yes yes Comp # 3061-64F Colorsl yellow sl yellow sl yellow Appearance clear clear clear Uniform? yesyes yes

Example 8 Preparation of a Dual Chamber Insecticide FormulationContaining Permethrin, Dinotefuran and Pyriproxyfen

The following materials were added to the mixture to a finalconcentration of the indicated percentages by weight.

TABLE 4 Ingredients CAS# % by weight Chamber 1 Ethyl Lactate 97-64-354.028 (± 9.0 variation acceptable) Permethrin 52645-53-1 45.972 (± 9.0variation acceptable) Chamber 2 Ethyl Lactate 97-64-3 47.8 (± 4.0variation acceptable) Dinotefuran 165252-70-0 15.0 (± 3.0 variationacceptable) Pyriproxyfen 95737-68-1 1.5 (± 0.3 variation acceptable)Casto Oil, hydrogenated, 61788-85-0 7.5 (± 1.0 variation ethoxylatedacceptable) Polyvinylpyrrolidone-vinyl 25086-89-9 1.5 (± 0.3 variationacetate copolymer (50% in acceptable) water) Vitamin E Acetate 58-95-72.5 (± 0.5 variation acceptable) N-octyl-2-pyrrolidone (NOP) 2687-94-70.2 (± 0.02 variation acceptable) Citric Acid 77-92-9 0.01 (± 0.001variation acceptable) Citric Acid, trisodium salt 68-04-2 0.11 (± 0.01variation acceptable) Deionized Water 7732-18-0 22.88 (± 4.0 variationacceptable) Sodium bis(2-ethyl hexyl) 577-11-7 1.0 (± 0.02 variationsulfosuccinate (75% solution acceptable) in water)

Example 9 Preparation of an Insecticide Formulation ContainingPermethrin, Dinotefuran and Pyriproxyfen

The following materials were added to the mixture to a finalconcentration of the indicated percentages by weight.

TABLE 5 Ingredients CAS# % by weight Permethrin 52645-53-1 36.880 (± 5.0variation acceptable) Dinotefuran 165252-70-0 5.0 (± 2.0 variationacceptable) Pyriproxyfen 95737-68-1 0.45 (± 0.1 variation acceptable)N-octyl-2-pyrrolidone (NOP) 2687-94-7 6.0 (± 1.5 variation acceptable)N-methyl pyrrilodione (NMP) 872-50-4 51.670 (± 6.0 variation acceptable)

Example 10 Analysis of Active Ingredient Concentration Over Time atVariable Temperatures

The formulation of Example 9 was stored under variable temperatures upto 6 months to determine the stability of dinotefuran, pyriproxyfen andpermethrin in solution. The results (in average percent by weight) areshown in Tables 6-9 below.

TABLE 6 Polypropylene Tubes 130° F. 40° C. 40° C. 40° C. RT RT INITIAL 1Month 2 Months 4 Months 6 Months 3 Months 6 Months Dinotefuran 4.99 4.734.93 4.70 4.80 4.96 4.92 Pyriproxyfen 0.44 0.45 0.46 0.43 0.46 0.44 0.43Permethrin 35.51 35.45 35.95 36.63 37.13 35.64 35.33

TABLE 7 Polypropylene Tubes 130° F. 40° C. 40° C. 40° C. RT RT INITIAL 1Month 2 Months 4 Months 6 Months 3 Months 6 Months Dinotefuran 5.02 4.674.90 4.65 4.63 4.97 4.92 Pyriproxyfen 0.45 0.44 0.45 0.43 0.45 0.44 0.43Permethrin 36.06 35.09 35.60 36.21 36.35 35.56 36.13

TABLE 8 Polypropylene Tubes 130 ° F. 40 ° C. 40° C. 40° C. RT RT INITIAL1 Month 2 Months 4 Months 6 Months 3 Months 6 Months Dinotefuran 4.994.73 5.00 4.68 4.91 4.97 4.97 Pyriproxyfen 0.44 0.46 0.44 0.45 0.46 0.440.43 Permethrin 35.72 36.34 35.70 37.35 37.47 35.87 35.86

TABLE 9 Polypropylene Tubes 130 ° F. 40 ° C. 40 ° C. 40 ° C. RT RTINITIAL 1 Month 2 Months 4 Months 6 Months 3 Months 6 Months Dinotefuran5.01 5.09 5.03 5.01 5.08 4.99 5.06 Pyriproxyfen 0.45 0.44 0.44 0.43 0.430.44 0.43 Permethrin 35.92 36.25 35.41 36.66 36.37 36.32 36.32

It can be seen that insecticides in accordance with the invention canremain liquids, without readily observable precipitation (e.g., visiblecrystal formation), at room temperature, preferably less than about 4°C. and more preferably under about 0° C. for more than 4 days,preferably more than 6 months.

It will thus be seen that the objects set forth above, among those madeapparent from the preceding description, are efficiently attained and,since certain changes may be made in carrying out the above method andin the composition set forth without departing from the spirit and scopeof the invention, it is intended that all matter contained in the abovedescription shall be interpreted as illustrative and not in a limitingsense.

It is also to be understood that the following embodiments are intendedto cover all of the generic and specific features of the inventionherein described and all statements of the scope of the invention which,as a matter of language, might be said to fall therebetween.

Particularly it is to be understood that in said embodiments,ingredients or compounds recited in the singular are intended to includecompatible mixtures of such ingredients wherever the sense permits.

1. An insecticide formulated by combining about 37 to 38% permethrin;about 5 to 10% dinotefuran; an effective amount of pyriproxyfen; and aneffective amount of a solvent component comprising N-octyl pyrrolidoneand N-methyl pyrrolidone.
 2. The insecticide of claim 1, wherein theinsecticide comprises about 0.45 to 5% pyriproxyfen.
 3. The insecticideof claim 1, wherein the insecticide comprises no more than 6% N-octylpyrrolidone.
 4. The insecticide of claim 1, wherein the insecticidecomprises about 41 to 57% N-methylpyrrolidone.
 5. The insecticide ofclaim 1, wherein the insecticide comprises about 37% permethrin.
 6. Theinsecticide of claim 5, wherein the insecticide comprises about 5%dinotefuran.
 7. The insecticide of claim 6, wherein the insecticidecomprises about 0.45% pyriproxyfen.
 8. The insecticide of claim 7,wherein the insecticide comprises no more than 6% N-octyl pyrrolidone.9. The insecticide of claim 8, wherein the insecticide comprises about51 to 57% N-methylpyrrolidone.
 10. The insecticide of claim 1, whereinthe insecticide comprises about 37.08% permethrin.
 11. The insecticideof claim 10, wherein the insecticide comprises about 7.5 to 10%dinotefuran.
 12. The insecticide of claim 11, wherein the insecticidecomprises about 1 to 5% pyriproxyfen.
 13. The insecticide of claim 12,wherein the insecticide comprises no more than 6% N-octyl pyrrolidone.14. The insecticide of claim 13, wherein the insecticide comprises about41 to 55% N-methylpyrrolidone.
 15. The insecticide of claim 1, whereinthe insecticide comprises about 5% dinotefuran.
 16. The insecticide ofclaim 15, wherein the insecticide comprises no more than 6% N-octylpyrrolidone.
 17. The insecticide of claim 16, wherein the insecticidecomprises about 46 to 57% N-methyl pyrrolidone.
 18. The insecticide ofclaim 1, wherein the insecticide comprises about 1 to 5% pyriproxyfen.